Cholinergic agents

A central tenet of Alzheimer disease (AD) is the loss of cortical cholinergic function and cholinergic markers in postmortem brain specimens. Whether these profound deficits in cholinergic markers found in end-stage patients are also found in patients with much earlier disease is not known. To determine whether cholinergic deficits in AD precede, follow, or occur in synchrony with the earliest signs of cognitive deterioration. Postmortem study of nursing home residents with Clinical Dementia Rating (CDR) Scale scores of 0.0 to 2.0 and 4.0 to 5.0 who underwent autopsy between 1986 and 1997, comparing the activity of the cholinergic marker enzymes in the cortices of 66 elderly subjects with no (CDR score = 0.0; n = 18), questionable (CDR score = 0.5; n = 11), mild (CDR score = 1.0; n = 22), or moderate (CDR score = 2.0; n = 15) dementia vs subjects with severe dementia (CDR score = 4.0-5.0; n = 15). Activity of the cholinergic marker enzymes choline acetyltransferase and acetylcholine...

The cellular mechanisms by which neuronal nicotinic cholinergic receptors influence many aspects of physiology and pathology in the neocortex remain primarily unknown. Whole-cell recordings and single-cell reverse transcription (RT)-PCR were combined to analyze the effect of nicotinic receptor agonists on different types of neurons in acute slices of rat neocortex. Nicotinic receptor agonists had no effect on pyramidal neurons and on most types of interneurons, including parvalbumin-expressing fast spiking interneurons and somatostatin-expressing interneurons, but selectively excited a subpopulation of interneurons coexpressing the neuropeptides vasoactive intestinal peptide (VIP) and cholecystokinin. This excitation persisted in the presence of glutamate, GABA, and muscarinic receptor antagonists and in the presence of tetrodotoxin and low extracellular calcium, suggesting that the depolarization was mediated through the direct activation of postsynaptic nicotinic receptors. The re...

Cortical cholinergic inputs are hypothesized to mediate atten- tional functions. The present experiment was designed to de- termine the single unit activity of neurons within the medial prefrontal cortex (mPFC) of rats performing a sustained visual attention task. Demands on attentional performance were var- ied by the presentation of a visual distractor. The contribution of cholinergic afferents of the mPFC

Inflammatory markers are increased systematically and locally (e.g., skeletal muscle) in stroke patients. Besides being associated with cardiovascular risk factors, proinflammatory cytokines seem to play a key role in muscle atrophy by regulating the pathways involved in this condition. As such, they may cause severe decrease in muscle strength and power, as well as impairment in cardiorespiratory fitness. On the other hand, physical exercise (PE) has been widely suggested as a powerful tool for treating stroke patients, since PE is able to regenerate, even if partially, physical and cognitive functions. However, the mechanisms underlying the beneficial effects of physical exercise in poststroke patients remain poorly understood. Thus, in this study we analyze the candidate mechanisms associated with muscle atrophy in stroke patients, as well as the modulatory effect of inflammation in this condition. Later, we suggest the two strongest anti-inflammatory candidate mechanisms, myokin...

Alzheimer's disease (AD), the most common form of dementia among the elderly, is a progressive, degenerative disorder of the brain with a loss of memory and cognition. A defining characteristic of AD is the deposition of amyloid fibrils and neurofibrillary tangles in the brain of afflicted individuals. Biochemically, they are mainly composed of β-amyloid protein (Aβ) and phosphorylated tau proteins, respectively. There is also a loss of the presynaptic markers of the cholinergic system, such as acetylcholine, in the brain areas related to memory and learning. The biochemical pathways leading to AD are presently unknown and are a subject of intensive study with current theories favoring a hypothesis where Aβ aggregates to toxic forms that induce tau phosphorylation and aggregation. It is believed that this ultimately leads to dysfunction and death of cholinergic neurons, and compensation for this loss had been the primary focus of first generation therapeutic agents. The amyloid and tau hypotheses have lead to a focus on amyloid and tau as therapeutic targets. The current therapeutic goals are to reduce amyloid levels, prevention of amyloid aggregation/toxicity and tau phosphorylation/aggregation. AD has a heterogeneous etiology with a large percentage termed sporadic AD arising from unknown causes and a smaller fraction of early onset familial AD (FAD) caused by mutations in several genes, such as the β-amyloid precursor protein (APP) and presenilins (PS1, PS2). Other genes, such as apolipoprotein E (APOE), are considered to be risk factors for AD. Several proteins, such as APP, APOE, BACE (β-amyloid cleaving enzyme), PS1/2, secretases, and tau play important roles in the pathology of AD. Therefore, attempts are being made to develop new inhibitors for BACE, PS-1 and γ-secretase for treatment of AD. There is also a significant advancement in understanding the function of cholinesterase (ChE) in the brain and the use of ChE inhibitors in AD. The mechanism of a new generation of acetyl- and butyrylChE inhibitors is being studied and tested in human clinical trials for AD. Other strategies, such as vaccination, anti-inflammatory agents, cholesterol-lowering agents, anti-oxidants and hormone therapy, are also being studied for treating or slowing the progression of AD. Developments of early diagnostic tools based on quantitative biochemical markers will be useful to better follow the course of the disease and to evaluate different therapeutic strategies. In the present review, we attempt to critically examine recent trends in AD research from neurochemical to clinical areas. We analyze various neurobiological mechanisms that provide the basis of new targets for AD drug development. These current research efforts should lead to a deeper understanding of the pathobiochemical processes that occur in the AD brain to effectively diagnose and prevent their occurrence. Drug Dev. Res. 56:267–281, 2002. © 2002 Wiley-Liss, Inc.

Co-occurrence of tobacco smoking and alcohol consumption during adolescence is frequent and well documented. However, little is known about the basic neurobiology of the combined exposure in the adolescent brain. Since nicotine is a cholinergic agonist and it has been shown that ethanol interferes with nicotinic acetylcholine receptors (nAChRs), the current work focused on cholinergic systems. From the 30th to the 45th postnatal day (PN), C57BL/6 male and female mice were exposed to nicotine free base (NIC) and/or ethanol (ETOH). Four groups were analyzed: 1) concomitant NIC (50 μg/ml in 2% saccharin to drink) and ETOH (25%, 2 g/kg i.p. injected every other day) exposure; 2) NIC exposure; 3) ETOH exposure; 4) vehicle. We assessed nAChR binding, choline acetyltransferase (ChAT) activity and [3H]hemicholinium-3 (HC-3) binding in the cerebral cortex and midbrain of mice on PN45. In the cortex, ETOH had no effect on nAChRs. In contrast, NIC produced nAChR upregulation while NIC + ETOH elicited a more pronounced effect. In the midbrain, neither ETOH nor NIC had effects on nAChRs. NIC + ETOH, however, elicited a robust nAChR upregulation. Regarding ChAT activity, treatment effects differed between males and females in the cortex. Male NIC mice presented an increase in ChAT. However, ETOH reversed this effect. In contrast, female NIC mice presented decreased ChAT activity. In the midbrain, ETOH increased ChAT. HC-3 binding was not affected. These results indicate that the central cholinergic system is a site at which nicotine and ethanol interact. This interaction might underlie the association between tobacco and alcohol consumption during adolescence.

Traumatic brain injury (TBI), often caused by a concussive impact to the head, affects an estimated 1.7 million Americans annually. With no approved drugs, its pharmacological treatment represents a significant and currently unmet medical need. In our prior development of the anti-cholinesterase compound phenserine for the treatment of neurodegenerative disorders, we recognized that it also possesses non-cholinergic actions with clinical potential. Here, we demonstrate neuroprotective actions of phenserine in neuronal cultures challenged with oxidative stress and glutamate excitotoxicity, two insults of relevance to TBI. These actions translated into amelioration of spatial and visual memory impairments in a mouse model of closed head mild TBI (mTBI) two days following cessation of clinically translatable dosing with phenserine (2.5 and 5.0 mg/kg BID x 5 days initiated post mTBI) in the absence of anti-cholinesterase activity. mTBI elevated levels of thiobarbituric acid reactive sub...

Rationale In schizophrenia, attentional disturbance is a core feature which may not only accompany the disorder, but may precede the onset of psychiatric symptoms. Objectives The five-choice serial reaction time task (5CSRTT) is a test of visuo-spatial attention that has been used extensively in rats for measuring the effects of systemic and central neurochemical manipulations on various aspects of attentional performance, including selective attention, vigilance and executive control. These findings are relevant to our understanding of the neural systems that may be compromised in patients with schizophrenia. Methods The 5CSRTT is conducted in an operant chamber that has multiple response locations, in which brief visual stimuli can be presented randomly. Performance is maintained using food reinforcers to criterion levels of accuracy. Various aspects of performance are measured, including attentional accuracy and premature responding, especially under different attentional challenges. Results The effects of systemic and intra-cerebral infusions of selective dopamine, serotonin and cholinergic receptor agents on the 5CSRTT are reviewed with a view to identifying attention-enhancing effects that may be relevant to the treatment of cognitive deficits in schizophrenia. In addition, some novel agents such as modafinil and histamine receptor agents are also considered. Examining the effects of selective neurochemical lesions helped define the neural locus of attentional effects. Similarly, findings from microdialysis studies helped identify the extracellular changes in neurotransmitters and their metabolites in freely moving rats during performance of the 5CSRTT. Conclusions The monoaminergic and cholinergic systems have independent but complementary roles in attentional function, as measured by the 5CSRTT. These functions are predominantly under the control of the prefrontal cortex and striatum. These conclusions are considered in the context of their application towards therapeutic approaches for attentional disturbances that are typically observed in schizophrenic patients.

Until recently our understanding of the functional neuroanatomy of the cholinergic basal forebrain (CBF) has been hindered by the lack of a lesioning technique that is truly selective. The development of the immunotoxin 192 IgG-saporin (192-sap) has greatly improved our ability to create specific lesions of the CBF. Rats with such lesions have been studied in a wide variety of behavioral paradigms of learning, memory, and attention. Complete or near-complete destruction of the CBF results in deficits in a variety of behavior paradigms including passive avoidance, spatial tasks (water and radial mazes), delayed matching to position/sample, and attentional tasks. However, interpretation of many experiments is hampered by incomplete lesions and/or concomitant damage to cerebellar Purkinje neurons. Future studies will need to address these issues. Recent development of a similar immunotoxin that is effective in primates should permit more sophisticated behavioral analysis of CBF functio...

The purpose of our work was to investigate how the cholinergic environment influences the targeting and the intracellular trafficking of the muscarinic receptor m2 (m2R) in vivo. To address this question, we have used immunohistochemical approaches at light and electron microscopic levels to detect the m2R in control rats and rats treated with muscarinic receptor agonists. In control animals, m2Rs were located mostly at postsynaptic sites at the plasma membrane of perikarya and dendrites of cholinergic and NPY-somatostatin interneurons as autoreceptors and heteroreceptors, respectively. Presynaptic receptors were also detected in boutons. The m2Rs were usually detected at extrasynaptic sites, but they could be found rarely in association with symmetrical synapses, suggesting that the cholinergic transmission mediated by m2R occurs via synaptic and nonsynaptic mechanisms. The stimulation of muscarinic receptors with oxotremorine provoked a dramatic alteration of m2R compartmentalizat...

Methyllycaconitine (MLA), α -conotoxin IMI, and α -bungarotoxin inhibited the release of catecholamines triggered by brief pulses of acetylcholine (ACh) (100 μ M, 5 s) applied to fast-superfused bovine adrenal chromaffin cells, with IC50s of 100 nM for MLA and 300 nM for α -conotoxin ImI and α -bungarotoxin. MLA (100 nM), α -conotoxin ImI (μ M), and α -bungarotoxin (1 μ M) halved the entry of 45Ca2+ stimulated by 5-s pulses of 300 μ M ACh applied to incubated cells. These supramaximal concentrations of α 7 nicotinic receptor blockers depressed by 30% (MLA), 25% (α -bungarotoxin), and 50% (α -conotoxin ImI) the inward current generated by 1-s pulses of 100 μ M ACh, applied to voltageclamped chromaffin cells. In Xenopus oocytes expressing rat brain α 7 neuronal nicotinic receptor for acetylcholine nAChR, the current generated by 1-s pulses of ACh was blocked by MLA, α -conotoxin ImI, and α -bungarotoxin with IC50s of 0.1 nM, 100 nM, and 1.6 nM, respectively; the current through α 3β 4 nAChR was unaffected by α -conotoxin ImI and α -bungarotoxin, and weakly blocked by MLA (IC50 = 1 μ M). The functions of controlling the electrical activity, the entry of Ca2+, and the ensuing exocytotic response of chromaffin cells were until now exclusively attributed to α 3β 4 nAChR; the present results constitute the first evidence to support a prominent role of α 7 nAChR in controlling such functions, specially under the more physiological conditions used here to stimulate chromaffin cells with brief pulses of ACh.